Through long evolution, the human body has developed very sophisticated, complex and effective defense mechanisms against injury and disease. Nevertheless, sometimes these mechanisms can result in undesirable consequences, as, for example, when histamines are liberated in response to an allergen, or when transplanted organs are rejected by the immune system.
Perhaps the most common defense mechanism is the replacement of tissue when cells are destroyed by injury or disease. This mechanism can also engender phenomena which are, in effect, counter-productive. Whereas the normal acute inflammatory reaction in response to cellular injury is essential to survival in traumatic situations, that same mechanism can lead to an excessive response which exceeds its intent. Examples of these excessive responses include keloids of the skin, adhesions of organs to surrounding tissues following injury or surgery, stricture formation in hollow conduits such as ureters, fallopian tubes, and bile ducts, and contractures surrounding implantable medical devices.
The trauma induced by the well-known procedures of angioplasty or stenting for treatment of flow restrictions in the cardiovascular system can result in failure of the procedure by restenosis, or blockage, of the vessel soon afterwards. Vascular grafts used to relieve blood flow restrictions, to treat aneurysms, or to provide access for conduits needed for dialysis also can become blocked by intimal hyperplasia, or cellular proliferation, after insertion of the graft into the body. Even surgery on the skin can result in the undesirable phenomenon of scar tissue formation which, while seldom life-threatening, can result in disfigurement. All of these phenomena are manifested by a proliferation of cells, typically smooth muscle cells and/or fibroblasts, to an extent which exceeds the requirement for successful healing of the injury.
It has been discovered that ionizing radiation can address and temper the crucial final mechanism of restenosis. Radiation inhibits cell proliferation by preventing replication and migration of cells and by inducing programmed cell death (apoptosis).
Cells are variably susceptible to radiation, dependent on the types of cells and their proliferative status. Rapidly proliferating cells are generally more radiation-sensitive, whereas quiescent cells are more radiation-tolerant. High doses of radiation can kill all functions of even quiescent cells, whereas lower levels can merely lead to division delays. However, the desirable effect of reproductive death still obtains. In this case, the cell remains structurally intact but has lost its ability to proliferate, or divide indefinitely. It appears that low level radiation produces this desirable effect without causing tissue destruction or wasting (atrophy). In addition, the choice of isotopes allows for the local application of predictable doses of radiation with known depths of penetration and times of application, which are the factors that govern the biological effects of radiation.
Radiation treatment (usually known as "brachytherapy" when used for cancer treatment) is well-established for the treatment of cancer, a malignant form of cellular proliferation. Radiation treatment is also generally considered by the medical community to be effective in controlling the healing response. In particular, there appears to be general agreement among the interventional cardiology community that focused interluminal radiation can significantly reduce the restenosis problem.
Abbass et al., in their pioneering work, showed the effect of external radiation in retarding cell proliferation following percutaneous transluminal coronary angioplasty (PTCA). To avoid the complexities involved in the use of external radiation sources, several groups have investigated the brachytherapy approach by using an internal source of radiation. In particular, Fischell et al. have shown that the use of low-intensity (on the order of 10 microcuries, which is less radiation than the amount of radiation involved with angiography), low-energy beta emitters (average energy of 0.69 MeV) and short-lived (14.3 day half life).sup.32 p in animal studies have significantly reduced neointimal regrowth. Similarly, the effectiveness of brachytherapy in connection with the interoperative use of a radioactive coronary guidewire to retard intimal hyperplasia is known. For example, U.S. Pat. No. 5,498,227 to Mawad discloses the use of a radioactive wire intended for use in the delivery of a dose of radiation to a lesion or other body tissue. The wire includes an inner radioactive core surrounded by an outer buffer layer of platinum or other high atomic number metal to attenuate the radiation. The wire is made radioactive by incubation in a nuclear accelerator for a specified period of time prior to its implantation into the body.
Attention is currently being directed to the practical aspects of the use of brachytherapy. These aspects are, of course, particularly significant when radioactivity is involved. A portion of the patient may be exposed to radiation either before or during an operative procedure. Alternatively, the radioactivity may be incorporated into an implanted device. In the first case, higher intensities of radiation are needed, which pose safety and handling problems. In the second case, the implanted devices are typically quite expensive. If radioactivity is added to the device, it is only effective during a relatively short period during which the radioactivity is provided at a useful (therapeutic) level. The device is not useful if the radioactivity has decayed to a level which is below the therapeutic minimum dosage level. Depending on the radioisotope used, the decay time may be in hours, days or weeks.
Currently, despite the rapidly increasing interest in the use of low-level radioactivity for the inhibition of cellular proliferation, there is no commercial source of radionuclide ion implantation for medical devices anywhere in the world. The rapidity with which this need is developing is evidenced from numerous publications, well-attended conferences and clinical studies now under way. Despite the obvious potential improvement in medical economics and patient outcomes represented by these applications, their approaching commercialization will impose a manufacturing requirement that is as yet unfulfilled in any practical manner.
Although there still remain proponents of the use of external radiation beams for this purpose, most prospective users and suppliers involved with intervascular radiotherapy would prefer to use only the minimum level of radioactivity necessary for effectiveness. This requires that the radioisotope be as localized as possible, preferably incorporated into a surgical fastening device (such as a suture, staple, clip, pin, plate, graft, or patch, etc.) which closely approximates the site to be treated.
It is known to use a surgical suture in combination with a radiation source in order to apply a therapeutic dose of radiation to a specific treatment site for cancer treatment. For example, U.S. Pat. No. 2,153,889 to Hames discloses a nonabsorbable tubular woven suture material which acts as a carrier vehicle for discrete radioactive seeds, which are spaced apart from one another along a length of the suture. The radioactive seeds are maintained in place at the treatment site with the suture until the desired radiation dose is delivered, after which the suture is withdrawn. U.S. Pat. No. 4,509,506 to Windorski et al. discloses an absorbable suture material which contains and acts as a carrier vehicle for radioactive seeds for cancer treatment.
A disadvantage of these prior art sutures is that, because they are merely carrier vehicles for radioactive seeds, the seeds must be specifically placed and distributed in a desired spacing along the sutures. This requires substantial labor in the manufacture of the suture. In addition, the radiation dose is nonuniformly distributed to the treatment region as a result of the spacing between radioactive seeds in the suture. Other problems include the relatively large diameter required for a suture which must contain the radioactive seeds within an inner lumen. The possibility exists that the radioactive seeds within the inner lumen will become dislodged, resulting in the migration and leaching of radioactivity into tissues remote from the treatment site.
The provision of other types of surgical fastening devices, including staples, clips, pins, plates and patches, in combination with a source of radiation would be an advancement in the art.
The incorporation of a source of radiation into a polymeric carrier is also known. U.S. Pat. No. 5,199,939 to Dake et al. discloses an elongated catheter or carrier which houses a radiation source, which can be placed onto or into the carrier or manufactured into the material of the carrier. Integration of a radioisotope into the material of a metallic stent is also known. See, for example, U.S. Pat. Nos. 5,059,166 and 5,176,617 to Fischell et al., which disclose the integration of a radioisotope into the stent material by alloying or coating processes. It is further known to employ ion implantation methods to integrate metal atoms into nonmetallic substrates. See, for example, U.S. Pat. No. 5,520,664 to Bricault, Jr. et al., which discloses the use of ion beam assisted deposition (IBAD) techniques to incorporate an antimicrobial metal, such as silver, into the surface of a polymeric catheter.
However, the use of ion implantation methods to incorporate a radioisotope into various metallic and nonmetallic surgical fastening devices has been heretofore unknown.